On the Particle Data Group evaluation of Psi' and chi_c Branching Ratios

I propose a new evaluation of $\psi'(2S)$ and $\chi_c(1P)$ branching ratios which avoids the correlations affecting the current Particle Data Group evaluation. These correlations explain the apparent technique-dependent discrepancies between the available determinations of the ${\cal B}(\chi_c(1P)\to p\bar p)$ and $\Gamma(\chi_c(1P)\to \gamma\gamma)$ under the hypotesis that the current values of the $\psi'(2S)\to\chi_c(1P)\gamma$ branching ratios are overestimated. In the process I also noticed that Particle Data Group has not restated many of the older measurements, when necessary, for the new value of ${\cal B}(J/\psi\to l^+l^-)$, which significantly affects the evaluation of some relevant $\psi'(2S)$ and $\chi_c(1P)$ exclusive branching ratios.Comment: 13 pages. Revised version. Submitted to Phys. Rev.

Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain

Background: Descending facilitation, from the brainstem, promotes spinal neuronal hyperexcitability and behavioural hypersensitivity in many chronic pain states. We have previously demonstrated enhanced descending facilitation onto dorsal horn neurones in a neuropathic pain model, and shown this to enable the analgesic effectiveness of gabapentin. Here we have tested if this hypothesis applies to other pain states by using a combination of approaches in a rat model of osteoarthritis (OA) to ascertain if 1) a role for descending 5HT mediated facilitation exists, and 2) if pregabalin (a newer analogue of gabapentin) is an effective antinociceptive agent in this model. Further, quantitative-PCR experiments were undertaken to analyse the alpha(2)delta-1 and 5-HT3A subunit mRNA levels in L3-6 DRG in order to assess whether changes in these molecular substrates have a bearing on the pharmacological effects of ondansetron and pregabalin in OA.Results: Osteoarthritis was induced via intra-articular injection of monosodium iodoacetate (MIA) into the knee joint. Control animals were injected with 0.9% saline. Two weeks later in vivo electrophysiology was performed, comparing the effects of spinal ondansetron (10-100 mu g/50 mu l) or systemic pregabalin (0.3-10 mg/kg) on evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimuli in MIA or control rats. In MIA rats, ondansetron significantly inhibited the evoked responses to both innocuous and noxious natural evoked neuronal responses, whereas only inhibition of noxious evoked responses was seen in controls. Pregabalin significantly inhibited neuronal responses in the MIA rats only; this effect was blocked by a pre-administration of spinal ondansetron. Analysis of alpha(2)delta-1 and 5-HT3A subunit mRNA levels in L3-6 DRG revealed a significant increase in alpha(2)delta-1 levels in ipsilateral L3&4 DRG in MIA rats. 5-HT3A subunit mRNA levels were unchanged.Conclusion: These data suggest descending serotonergic facilitation plays a role in mediating the brush and innocuous mechanical punctate evoked neuronal responses in MIA rats, suggesting an adaptive change in the excitatory serotonergic drive modulating low threshold evoked neuronal responses in MIA-induced OA pain. This alteration in excitatory serotonergic drive, alongside an increase in alpha(2)delta-1 mRNA levels, may underlie pregabalin's state dependent effects in this model of chronic pain

CACHD1 is an α2δ-like protein that modulates CaV3 voltage-gated calcium channel activity

The putative cache (Ca2+ channel and chemotaxis receptor) domain containing 1 (CACHD1) protein has predicted structural similarities to members of the alpha2delta voltage-gated Ca2+ channel (VGCC) auxiliary subunit family. CACHD1 mRNA and protein were highly expressed in the male mammalian CNS, in particular in the thalamus, hippocampus and cerebellum, with a broadly similar tissue distribution to CaV3 subunits, in particular, CaV3.1. In expression studies, CACHD1 increased cell-surface localization of CaV3.1 and these proteins were in close proximity at the cell surface consistent with the formation of CACHD1-CaV3.1 complexes. In functional electrophysiological studies, co-expression of human CACHD1 with CaV3.1, CaV3.2 and CaV3.3 caused a significant increase in peak current density and corresponding increases in maximal conductance. By contrast, alpha2delta-1 had no effect on peak current density or maximal conductance in either CaV3.1, CaV3.2 or CaV3.3. Comparison of CACHD1-mediated increases in CaV3.1 current density and gating currents revealed an increase in channel open probability. In hippocampal neurons from male and female E19 rats, CACHD1 overexpression increased CaV3-mediated action potential (AP) firing frequency and neuronal excitability. These data suggest that CACHD1 is structurally an alpha2delta-like protein that functionally modulates CaV3 voltage-gated calcium channel activity

Synaptopathies: Dysfunction of Synaptic Function The anti-allodynic α 2 δ ligand pregabalin inhibits the trafficking of the calcium channel α 2 δ-1 subunit to presynaptic terminals in vivo

Abstract Neuropathic pain is caused by lesion or dysfunction of the peripheral sensory nervous system. Up-regulation of the voltage-gated Ca 2+ channel subunit α 2 δ-1 in DRG (dorsal root ganglion) neurons and the spinal cord correlates with the onset of neuropathic pain symptoms such as allodynia in several animal models of neuropathic pain. The clinically important anti-allodynic drugs gabapentin and pregabalin are α 2 δ-1 ligands, but how these drugs alleviate neuropathic pain is poorly understood. In the present paper, we review recent advances in our understanding of their molecular mechanisms. Neuropathic pain Unlike nociceptive or acute pain, neuropathic pain occurs without continuous noxious peripheral input. Patients with neuropathic pain experience spontaneous pain that is described as 'electric-shock-like, burning and tingling'. Further symptoms of neuropathy are the painful response to normally innocuous stimuli (allodynia) and the increased response to noxious stimuli (hyperalgesia). In addition, patients also suffer from depression, anxiety and insomnia as a result of their chronic pain condition. A recent survey showed that up to 8 % of the population of the U.K. may endure chronic pain of predominantly neuropathic origin The axons of primary sensory afferents form the spinal nerves and dorsal roots, with their cell bodies residing within the DRGs (dorsal root ganglia

Global pressures, specific responses: effects of nutrient enrichment in streams from different biomes

Fil: Artigas, Joan. Clermont Université. Université Blaise Pascal. Laboratoire Microorganismes: Génome et Environnement; FranceFil: García-Berthou, Emili. Institute of Aquatic Ecology. University of Girona. Girona; SpainFil: Bauer, Delia Elena. Instituto de Limnología Dr. Raúl A. Ringuelet (ILPLA). Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Castro, Maria I.. Department of Biology. National University of Colombia. Bogotá DC; ColombiaFil: Cochero, Joaquín. Instituto de Limnología Dr. Raúl A. Ringuelet (ILPLA). Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Colautti, Darío César. Instituto de Limnología Dr. Raúl A. Ringuelet (ILPLA). Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Cortelezzi, Agustina. Instituto de Limnología Dr. Raúl A. Ringuelet (ILPLA). Facultad de Ciencias Naturales y Museo. Universidad Nacional de La PlataFil: Donato, John C.. Department of Biology. National University of Colombia. Bogotá DC; ColombiaFil: Elosegi, Arturo. Faculty of Science and Technology. The University of the Basque Country. Bilbao; SpainFil: Feijoó, Claudia S.. INEDES. Department of Basic Sciences. National University of Luján. Luján; ArgentinaFil: Giorgi, Adonis. INEDES. Department of Basic Sciences. National University of Luján. Luján; ArgentinaFil: Gómez, Nora. Institute of Aquatic Ecology. University of Girona. Girona; SpainFil: Leggieri, Leonardo. Institute of Aquatic Ecology. University of Girona. Girona; SpainFil: Muñoz, Isabel. Department of Ecology. University of Barcelona. Barcelona; SpainFil: Rodrigues Capítulo, Alberto. Instituto de Limnología Dr. Raúl A. Ringuelet (ILPLA). Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Romaní, Anna M.. Institute of Aquatic Ecology. University of Girona. Girona; SpainFil: Sabater, Sergi. Catalan Institute for Water Research (ICRA). Scientific and Technological Park of the University of Girona. Girona; Spai

Pregabalin Suppresses Spinal Neuronal Hyperexcitability and Visceral Hypersensitivity in the Absence of Peripheral Pathophysiology

ABSTRACT Background: Opioid-induced hyperalgesia is recognized in the laboratory and the clinic, generating central hyperexcitability in the absence of peripheral pathology. We investigated pregabalin, indicated for neuropathic pain, and ondansetron, a drug that disrupts descending serotonergic processing in the central nervous system, on spinal neuronal hyperexcitability and visceral hypersensitivity in a rat model of opioid-induced hyperalgesia. Methods: Male Sprague-Dawley rats (180 -200 g) were implanted with osmotic mini-pumps filled with morphine (90 g ⅐ l Ϫ1 ⅐

At a glance:the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years

Niemann-Pick type C1 disease (NPC1 [OMIM 257220]) is a rare and severe autosomal recessive disorder, characterized by a multitude of neurovisceral clinical manifestations and a fatal outcome with no effective treatment to date. Aiming to gain insights into the genetic aspects of the disease, clinical, genetic, and biomarker PPCS data from 602 patients referred from 47 countries and diagnosed with NPC1 in our laboratory were analyzed. Patients’ clinical data were dissected using Human Phenotype Ontology (HPO) terms, and genotype–phenotype analysis was performed. The median age at diagnosis was 10.6 years (range 0–64.5 years), with 287 unique pathogenic/likely pathogenic (P/LP) variants identified, expanding NPC1 allelic heterogeneity. Importantly, 73 P/LP variants were previously unpublished. The most frequent variants detected were: c.3019C &gt; G, p.(P1007A), c.3104C &gt; T, p.(A1035V), and c.2861C &gt; T, p.(S954L). Loss of function (LoF) variants were significantly associated with earlier age at diagnosis, highly increased biomarker levels, and a visceral phenotype (abnormal abdomen and liver morphology). On the other hand, the variants p.(P1007A) and p.(S954L) were significantly associated with later age at diagnosis (p &lt; 0.001) and mildly elevated biomarker levels (p ≤ 0.002), consistent with the juvenile/adult form of NPC1. In addition, p.(I1061T), p.(S954L), and p.(A1035V) were associated with abnormality of eye movements (vertical supranuclear gaze palsy, p ≤ 0.05). We describe the largest and most heterogenous cohort of NPC1 patients published to date. Our results suggest that besides its utility in variant classification, the biomarker PPCS might serve to indicate disease severity/progression. In addition, we establish new genotype–phenotype relationships for “frequent” NPC1 variants.</p

Molecular Gas in the NGC 6240 Merging Galaxy System at the Highest Spatial Resolution

We present the highest-resolution—15 pc (0.”03)—ALMA ¹²CO(2–1) line emission and 1.3 mm continuum maps, tracers of the molecular gas and dust, respectively, in the nearby merging galaxy system NGC 6240, which hosts two supermassive black holes growing simultaneously. These observations provide an excellent spatial match to existing Hubble Space Telescope (HST) optical and near-infrared observations of this system. A significant molecular gas mass, ~9 × 10⁹ M⊙, is located between the two nuclei, forming a clumpy stream kinematically dominated by turbulence, rather than a smooth rotating disk, as previously assumed from lower-resolution data. Evidence for rotation is seen in the gas surrounding the southern nucleus but not in the northern one. Dynamical shells can be seen, likely associated with nuclear supernova remnants. We further detect the presence of significant high-velocity outflows, some of them reaching velocities >500 km s⁻¹, affecting a significant fraction, ~11%, of the molecular gas in the nuclear region. Inside the spheres of influence of the northern and southern supermassive black holes, we find molecular masses of 7.4 × 10⁸ and 3.3 × 10⁹ M⊙, respectively. We are thus directly imaging the reservoir of gas that can accrete onto each supermassive black hole. These new ALMA maps highlight the critical need for high-resolution observations of molecular gas in order to understand the feeding of supermassive black holes and its connection to galaxy evolution in the context of a major galaxy merger